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Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of Intracranial Aneurysm

Romain Bourcier 1, 2 Solena Le Scouarnec 2 Stephanie Bonnaud 2, 1 Matilde Karakachoff 2, 1 Emmanuelle Bourcereau 1 Sandrine Heurtebise-Chrétien 2 Céline Menguy 2 Christian Dina 2, 1 Floriane Simonet 2, 1 Alexis Moles 1 Cédric Lenoble 1 Pierre Lindenbaum 2 Stéphanie Chatel 2, 1 Bertrand Isidor 1 Emmanuel Génin Jean-François Deleuze Jean-Jacques Schott 2, 1 Hervé Le Marec 2, 1 Gervaise Loirand 2 Hubert Desal 1, 2 Richard Redon 2, 1 Benjamin Daumas-Duport 1 Jérôme Connault 1 Pierre Lebranchu 3 Thierry Le Tourneau 2, 1 Pierre Viarouge Chrisanthi Papagiannaki Michel Piotin 4 Hocine Redjem 4 Mikael Mazighi 5 Jean-Philippe Desilles Olivier Naggara 6 Denis Trystram Myriam Edjlali-Goujon Christine Rodriguez Waghi Ben Hassen Suzanna Saleme Charbel Mounayer 7, 8 Olivier Levrier Pierre Aguettaz Xavier Combaz Anne Pasco Emeline Berthier Marc Bintner 9 Marc Molho Pascale Gauthier 10 Cyril Chivot Vincent Costalat Cyril Darganzil Alain Bonafé Anne Christine Januel 11 Caterina Michelozzi Christophe Cognard 12 Fabrice Bonneville 13 Philippe Tall Jean Darcourt Alessandra Biondi Cristina Iosif Elisa Pomero Jean-Christophe Ferre Jean Yves Gauvrit 14 François Eugène 15 Hélène Raoult Jean-Christophe Gentric Julien Ognard René Anxionnat 16, 17 Serge Bracard 16, 17 Anne Laure Derelle 18 Romain Tonnelet 19 Laurent Spelle Léon Ikka Robert Fahed 20 Aymeric Rouchaud Augustin Ozanne 21 Jildaz Caroff Nidal Ben Achour Jacques Moret Emmanuel Chabert Jérôme Berge Gaultier Marnat Xavier Barreau 22 Florent Gariel Frédéric Clarençon Mohammed Aggour Fréderic Ricolfi 23 Adrien Chavent 24 Pierre Thouant 25 Pablo Lebidinsky Brivael Lemogne Denis Herbreteau 26 Richard Bibi Laurent Pierot 27 Sébastien Soize Marc Antoine Labeyrie Christophe Vandendries Emmanuel Houdart 28 Appoline Kazemi Xavier Leclerc 29 Jean Pierre Pruvo Sophie Gallas Stéphane Velasco
24 Registre Dijonnais des Accidents Vasculaires Cérébraux (AVC) - Dijon Stroke Registry
CEP - Centre d'épidémiologie des populations, CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
Abstract : Intracranial aneurysms (IAs) are acquired cerebrovascular abnormalities characterized by localized dilation and wall thinning in intracranial arteries, possibly leading to subarachnoid hemorrhage and severe outcome in case of rupture. Here, we identified one rare nonsense variant (c.1378A>T) in the last exon of ANGPTL6 (Angiopoietin-Like 6)—which encodes a circulating pro-angiogenic factor mainly secreted from the liver—shared by the four tested affected members of a large pedigree with multiple IA-affected case subjects. We showed a 50% reduction of ANGPTL6 serum concentration in individuals heterozygous for the c.1378A>T allele (p.Lys460Ter) compared to relatives homozygous for the normal allele, probably due to the non-secretion of the truncated protein produced by the c.1378A>T transcripts. Sequencing ANGPTL6 in a series of 94 additional index case subjects with familial IA identified three other rare coding variants in five case subjects. Overall, we detected a significant enrichment (p = 0.023) in rare coding variants within this gene among the 95 index case subjects with familial IA, compared to a reference population of 404 individuals with French ancestry. Among the 6 recruited families, 12 out of 13 (92%) individuals carrying IA also carry such variants in ANGPTL6, versus 15 out of 41 (37%) unaffected ones. We observed a higher rate of individuals with a history of high blood pressure among affected versus healthy individuals carrying ANGPTL6 variants, suggesting that ANGPTL6 could trigger cerebrovascular lesions when combined with other risk factors such as hypertension. Altogether, our results indicate that rare coding variants in ANGPTL6 are causally related to familial forms of IA.
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Romain Bourcier, Solena Le Scouarnec, Stephanie Bonnaud, Matilde Karakachoff, Emmanuelle Bourcereau, et al.. Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of Intracranial Aneurysm. American Journal of Human Genetics, Elsevier (Cell Press), 2018, 102 (1), pp.133 - 141. ⟨10.1016/j.ajhg.2017.12.006⟩. ⟨hal-01808225⟩



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